Methods of preparing sulfinamides and sulfoxides

ABSTRACT

This invention encompasses novel methods of preparing sulfinamides and sulfoxides, particularly stereomerically pure sulfinamides and sulfoxides. The invention further encompasses novel compounds from which sulfinamides and sulfoxides can be prepared.

This application is a divisional of application Ser. No. 10/120,541filed on Apr. 12, 2002 now U.S. Pat. No. 7,064,214 the entirety of whichis incorporated herein by reference, which application Ser. No.10/120,541 claims priority to U.S. Provisional Application No.60/283,337, filed Apr. 13, 2001.

1. FIELD OF THE INVENTION

This invention relates to sulfinamides and sulfoxides, methods of theirpreparation, and compounds that can be used to prepare them.

2. BACKGROUND OF THE INVENTION 2.1. THE ASYMMETRIC SYNTHESIS OF AMINES

At least 75% of drugs and drug candidates reportedly incorporate aminefunctionality. Tang, T. P. and Ellman, J. A., J. Org. Chem. 64:12-13(1999). The asymmetric synthesis of amines is consequently of particularimportance to the pharmaceutical industry.

One method that reportedly can be used to prepare optically activeβ-amino acids is disclosed in International Application WO 2000/041997.According to this method, a compound of the formula RaC*H(OH)—C*H(Rb)Rc,wherein Rc can be R1SO₂(R2)N— and the asterisk signifies a chiralcenter, is reportedly prepared by reacting an α-aminocarbonyl compoundof the formula Ra—CO—CH(Rb)—Rc with hydrogen or a hydrogen donor in thepresence of an optically active transition metal compound and a base.

Another recently reported method of preparing chiral amino acidsutilizes sulfinamides. See, e.g., Tang, T. P. and Ellman, J. A., J. Org.Chem. 64:12-13 (1999); Cogen, D. A., et al., Tetrahedron 55:8883-8904(1999); Liu, G., et al., J. Am. Chem. Soc. 119:9913-9914 (1997); Davis,F. A. and McCoull, W., J. Org. Chem. 64:3396-3397 (1999). In an exampleof this method, tert-butanesulfinamide condenses with aldehydes andketones to give tert-butanesulfinyl imines in high yields. Tang, T. P.and Ellman, J. A., J. Org. Chem. 64:12-13 (1999). These imines can thenbe contacted with Grignard reagents or organolithiums to provide theintermediate shown below in Scheme I, which can then be subjected toacidic methanolysis to provide an a-branched amine-hydrochlorideproduct. Id.

Few methods of preparing enantiomerically pure sulfinamides have beenreported. See, e.g., Cogan, D. A., et al., J. Am. Chem. Soc.120:8011-8019 (1998); Liu, G., et al., J. Am. Chem. Soc. 119:9913-9914(1997). In one method, tert-butanesulfinamide is prepared byasymmetrically oxidizing tert-butyl disulfide to provide anintermediate, which is then cleaved by reaction with LiNH₂. Liu, G., etal., J. Am. Chem. Soc. 119:9913-9914 (1997). Unfortunately, theenantiomeric purity of the resulting sulfinamide reportedly does notexceed 91%. Id. The method is further limited in that it can be used forthe synthesis of only a few different kinds of sulfinamides, of whichtert-butanesulfinamide is an example. In addition, this method is notamenable to large-scale, or industrial, production of sulfinamides. Aneed therefore exits for more efficient and effective methods ofpreparing a wide variety of sulfinamides, particularly enantiomericallypure sulfinamides. A need further exists for a method of preparingsulfinamides that can be adapted to an industrial scale.

2.2. THE ASYMMETRIC SYNTHESIS OF SULFOXIDES

The synthesis of chiral sulfoxides is also important to thepharmaceutical industry. For example, a variety of pharmacologicallyactive benzimidazoles and structurally related sulfoxide compoundscontain a stereogenic sulfur atom. Examples of such compounds are shownbelow in racemic form:

Pantoprazole sodium is sold under the tradename Protonix® for the shortterm treatment of erosive esophagitis associated with gastroesophagealreflux disease (GERD). Physicians' Desk Reference, 3439-3442 (55th ed.,2001). Lansoprazole is sold under the tradename Prevacid® for the shortterm treatment of active duodenal ulcer. Id. at 3189-3194. Omeprazole,which is also indicated for the short term treatment of active duodenalulcer, is sold under the tradename Prilosec®. Id. at 587-591. Finally,rabeprazole is sold under the tradename Aciphex® for the short termtreatment of erosive or ulcerative GERD, for maintaining healing andreduction in relapse rates of heartburn symptoms in patients witherosive or ulcerative GERD, for the short-term healing of activeduodenal ulcer, and for the long-term treatment of pathologicalhypersecretroy conditions. Id. at 1178-1181.

Various attempts have been made to obtain enantiomerically pure forms ofsulfoxide compounds such as these. Initial attempts relied onchromatography and the formation of chiral salts. See, e.g., U.S. Pat.Nos. 5,693,818 and 5,714,504. Methods for the asymmetric syntheses ofsulfoxides have also been alleged. For example, U.S. Pat. No. 5,776,765discloses a process that can allegedly be used for the enantiomericsynthesis of omeprazole, which comprises the use of a microbial enzymesystem to enantioselectively reduce a racemic sulfoxide compound. See,e.g., col. 12, line 57- col. 13, line 67. A method disclosed by U.S.Pat. No. 5,948,789 comprises the oxidation of a pro-chiral sulphideusing a chiral titanium complex and a base. See, e.g., col. 25, line 64-col. 27, line 8.

A need exists for new methods of preparing stereomerically pure (e.g.,enantiomerically pure) sulfoxides. A particular need exists forefficient and effective methods of preparing enantiomerically puresulfoxides that can be adapted to an industrial scale.

3. SUMMARY OF THE INVENTION

This invention is directed, in part, to novel methods of preparingsulfmamides and sulfoxides, particularly stereomerically puresulfinamides and sulfoxides. The invention further encompasses novelcompounds from which sulfinamides and sulfoxides can be prepared.Compounds of this invention can be used in the preparation ofbiologically active (e.g., pharmacologically active) compounds, or arethemselves biologically active and useful in the treatment or preventionof diseases or conditions in animals (e.g., humans).

3.1. DEFINITIONS

As used herein, the term “prodrug” means a derivative of a compound thatcan hydrolyze, oxidize, or otherwise react under biological conditions(in vitro or in vivo) to provide the compound. Examples of prodrugsinclude, but are not limited to, derivatives of2-(2-pyridylmethyl)sulfinyl)benzimidazoles that comprise biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzableureides, and biohydrolyzable phosphate analogues. Other examples ofprodrugs include derivatives of2-(2-pyridylmethyl)suifinyl)-benzimidazoles that comprise —NO, —NO₂,—ONO, and —ONO₂ moieties.

As used herein, the terms “biohydrolyzable carbamate,” “biohydrolyzablecarbonate,” “biohydrolyzable ureide,” “biohydrolyzatle phosphate” mean acarbamate, carbonate, ureide, or phosphate, respectively, of a compoundthat either: 1) does not interfere with the biological activity of thecompound but can confer upon that compound advantageous properties invivo, such as uptake, duration of action, or onset of action; or 2) isbiologically less active or inactive but is converted in vivo to thebiologically active compound. Examples of biohydrolyzable carbamatesinclude, but are not limited to, lower alkylamines, substitutedethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic andheteroaromatic amines, and polyether amines.

As used herein, the term “biohydrolyzable ester” means an ester of acompound that either: 1) does not interfere with the biological activityof the compound but can confer upon that compound advantageousproperties in vivo, such as uptake, duration of action, or onset ofaction; or 2) is biologically less active or inactive but is convertedin vivo to the biologically active compound. Examples of biohydrolyzableesters include, but are not limited to, lower alkyl esters, acyl esters(e.g., —C(O)Z, wherein Z is F, C, Br, I), alkoxyacyloxy esters, alkylacylamino alkyl esters, and choline esters.

As used herein, the term “biohydrolyzable amide” means an amide of acompound that either: 1) does not interfere with the biological activityof the compound but can confer upon that compound advantageousproperties in vivo, such as uptake, duration of action, or onset ofaction; or 2) is biologically less active or inactive but is convertedin vivo to the biologically active compound. Examples of biohydrolyzableamides include, but are not limited to, lower alkyl amides, α-amino acidamides, alkoxyacyl amides, substituted and unsubstituted ureas, andalkylaminoalkylcarbonyl amides.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt prepared from a pharmaceutically acceptable non-toxic inorganic ororganic acid. Suitable non-toxic acids include, but are not limited to,acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,and p-toluenesulfonic acids. For example, specific pharmaceuticallyacceptable salts are hydrochloride, maleic acid, and tartaric acidsalts.

As used herein and unless otherwise indicated, the term “alkyl” includessaturated linear, branched, and cyclic hydrocarbon radicals having 1 to20 carbon atoms, 1 to 12, 1 to 8, or 1 to 4 carbon atoms. An alkyl groupcan include one or more double or triple bonds or can be substitutedwith one or more heteroatoms or halogens (e.g., F, Cl, Br, I). It isunderstood that cyclic alkyl groups comprise at least three carbonatoms. Specific examples of branched alkyl have one or two branches.Unsaturated alkyl have one or more double bonds and/or one or moretriple bonds. Specific examples of unsaturated alkyl have one or twodouble bonds or one triple bond. Alkyl chains may be unsubstituted orsubstituted with from 1 to 4 substituents. Specific examples ofsubstituted alkyl are mono-, di-, or trisubstituted alkyl. Specificexamples of alkyl substituents include halo, haloalkyl, hydroxy, aryl(e.g., phenyl, tolyl, alkyloxphenyl, alkyloxycarbonylphenyl,halophenyl), heterocyclyl, and heteroaryl.

As used herein and unless otherwise indicated, the term “lower alkyl”means branched or linear alkyl having from 1 to 8 or from 1 to 4 carbonatoms. Examples include, but are not limited to, methyl, ethyl, propyl,isopropyl, isobutyl, and tertiary butyl.

As used herein and unless otherwise indicated, the term “heteroalkyl”means a saturated or unsaturated chain containing carbon and at leastone heteroatom, wherein no two heteroatoms are adjacent. Heteroalkylchains contain from 1 to 18, 1 to 12, 1 to 6, or 1 to 4 member atoms(carbon and heteroatoms) in the chain. Heteroalkyl chains may bestraight or branched. Specific examples of branched heteroalkyl have oneor two branches. Unsaturated heteroalkyl have one or more double bondsand/or one or more triple bonds. Specific examples of unsaturatedheteroalkyl have one or two double bonds or one triple bond. Heteroalkylchains may be unsubstituted or substituted with from 1 to about 4substituents. Specific examples of heteroalkyl are substituted orunsubstituted. Specific examples of heteroalkyl substituents includehalo, hydroxy, aryl (e.g., phenyl, tolyl, alkyloxphenyl,alkyloxycarbonylphenyl, halophenyl), heterocyclyl, and heteroaryl. Forexample, alkyl substituted with the following substituents areheteroalkyl: alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy),aryloxy (e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy,benzyloxy, alkyloxycarbonylphenoxy, acyloxypfenoxy), acyloxy (e.g.,propionyloxy, benzoyloxy, acetoxy), carbamoyloxy, carboxy, mercapto,alkylthio, acylthio, arylthio (e.g., phenylthio, chlorophenylthio,alkylphenylthio, alkoxyphenylthio, benzylthio,alkyloxycarbonylphenylthio), amino (e.g., amino, mono- and di-C₁-C₃alkanylamino, methylphenylamino, methylbenzylamino, C₁-C₃ alkanylamido,carbamamido, ureido, guanidino).

As used herein and unless otherwise indicated, the term “heteroatom”includes a nitrogen, sulfur, oxygen, or phosphorus atom. Groupscontaining more than one heteroatom may contain different heteroatoms.

As used herein and unless otherwise indicated, the term “aryl” includesan organic radical derived from an aromatic hydrocarbon by removal ofone hydrogen, such as phenyl or naphthyl. Aryl rings are monocyclic orfused bicyclic ring systems. Monocyclic aromatic rings contain fromabout 5 to about 10 carbon atoms, from 5 to 7 carbon atoms, or from 5 to6 carbon atoms in the ring. Bicyclic aromatic rings contain from 8 to 12carbon atoms, or 9 or 10 carbon atoms in the ring. Aromatic rings may beunsubstituted or substituted with from 1 to about 4 substituents on thering. Specific examples of aromatic ring substituents include: halo,cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combinationthereof More Specific examples of substituents include halo andhaloalkyl. Specific examples of aromatic rings include naphthyl andphenyl.

As used herein and unless otherwise indicated, the term “aralkyl” meansan aryl substituted with one or more linear, branched, or cyclic alkylgroups. Aralkyl moieties can be attached to other moieties through theiraryl or alkyl components.

As used herein and unless otherwise indicated, the term “ether” includesalkyl groups wherein at least one carbon atom has been replaced with anoxygen atom, and aralkyl groups wherein at least one non-aromatic carbonatom-has been replaced with an oxygen atom.

As used herein and unless otherwise indicated, the terms “heterocyclicgroup” and “heterocycle” include aromatic and non-aromatic heterocyclicgroups containing one or more heteroatoms each selected from O, S, N, orP. Non-aromatic heterocyclic groups include groups having only 3 atomsin their ring system, but aromatic heterocyclic groups (i.e., heteroarylgroups) must have at least 5 atoms in their ring system. Heterocyclicgroups include benzo-fused ring systems and ring systems substitutedwith one or more oxo moieties. An example of a 4 membered heterocyclicgroup is azetidinyl (derived from azetidine). An example of a 5 memberedheterocyclic group is thiazolyl, and an example of a 10 memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclicgroups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,3H-indolyl, quinolizinyl, and substituted derivative thereof. Examplesof aromatic heterocyclic groups include, but are not limited to,pyridinyl, methylpyridine analgoues, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzoimidazoles, benzofuranyl, cinnolinyl, indazolyl,indolinyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, andsubstituted derivatives thereof. The foregoing groups, as derived fromthe compounds listed above, may be C-attached or N-attached where suchattachment is possible. For instance, a group derived from benzimidazolcan be benzimidazol-1-yl (N-attached) or benzimidazol-2-yl (C-attached).

As used herein and -unless otherwise indicated, the term “heteroaryl”means an aromatic heterocycle. A heteroaryl is an aromatic ring systemcontaining carbon and from 1 to about 4 heteroatoms in the ring.Heteroaromatic rings are monocyclic or fused bicyclic ring systems.Monocyclic heteroaromatic rings contain from about 5 to about 10, from 5to 7, or from 5 to 6 member atoms (carbon and heteroatoms). Bicyclicheteroaromatic rings contain from 8 to 12 9 or 10 member atoms.Heteroaromatic rings may be unsubstituted or substituted with from 1 toabout 4 substituents on the ring. Specific examples of heteroaromaticring substituents include: halo, cyano, alkyl, heteroalkyl, haloalkyl,phenyl, phenoxy or any combination thereof. More Specific examples ofsubstituents include halo, haloalkyl, and phenyl. Specific examples ofheteroaromatic rings include thienyl, thiazolo, purinyl, pyrimidyl,pyridyl, and furanyl.

As used herein and unless otherwise indicated, the term “sulfide”includes alkyl groups wherein at least one carbon atom has been replacedwith a sulfur atom, and aralkyl groups wherein at least one non-aromaticcarbon atom has been replaced with a sulfur atom.

As used herein and unless otherwise indicated, the term “substituted” asused to describe a compound or chemical moiety means that at least onehydrogen atom of that compound or chemical moiety is replaced with asecond chemical moiety. Examples of second chemical moieties include,but are not limited to: halogen atoms (e.g., chlorine, bromine, andiodine); C₁-C₆ linear, branched, or cyclic alkyl (e.g., methyl, ethyl,butyl, tert-butyl, and cyclobutyl); hydroxyl; thiols; carboxylic acids;esters, amides, silanes, nitriles, thioethers, stannanes, and primary,secondary, and tertiary amines (e.g., —NH₂, —NH(CH₃), —N(CH₃)₂, andcyclic amines). Specific examples of second chemical moieties arechlorine, hydroxyl, methoxy, amine, thiol, and carboxylic acid.

As used herein and unless otherwise indicated, a composition that is“substantially free” of a compound means that the composition containsless than about 20% by weight, more preferably less than about 10% byweight, even more preferably less than about 5% by weight, and mostpreferably less than about 3% by weight of the compound.

As used herein and unless otherwise indicated, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diasteroemers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of stereoisomer of the compound and less thanabout 20% by weight of other stereoisomers the compound, more preferablygreater than about 90% by weight of one stereoisomer of the compound andless than about 10% by weight of the other stereoisomers of thecompound, even more preferably greater than about 95% by weight of onestereoisomer of the compound and less than about 5% by weight of theother stereoisomers of the compound, and most preferably greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

As used herein and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center.

As used herein and unless otherwise indicated, the term “polymer bound”and “polymer bound alkyl or aryl” mean that the compound of theinvention is covalently bound to a polymer support, such as, but notlimited to, Merrifield Resin, See Wang et al., J. Org. Chem, 1977, 42,1286-1290; Wang Resin, See Fancelli et al., Tetrahedron Lett., 1997, 38,2311-2314; Aminomethyl Resin; MBHA Resin; Amino Acid-2-ChlorotritylResin; Carboxypolystyrene; 4-Nitrophenyl Carbonate Resin; Oxime Resin;Safety-Catch Resin; Alkenyl based resins; Br, Cl functionalized resins;Carbonate resins; CHO functionalized resins; CO₂H functionalized resins;Diazonium-based resins; Enol functionalized resins; NH₂, NH₂NHfunctionalized resins; OH functionalized resins; Orthogonalphotocleavable resins; SH functionalized resins; Silylalkyl resins;Silyloxy resins; Triazene-based resins; Polymer-bound bases (e.g.,(Polystyrylmethyl)trimethylammonium bicarbonate, Morpholinomethylpolystyrene HL, Piperazinomethyl polystyrene, Piperidine-4-carboxylicacid polyamine resin, Piperidinomethyl polystyrene, TBD-methylpolystyrene, Tris-(isonipecotylaminoethyl)-amine polystyrene);Polymer-bound coupling reagents (e.g., Ethoxycarbonylazocarboxymethylpolystyrene, HOBt-6-carboxamidomethyl polystyrene,N-Cyclohexylcarbodiimide,N′-methyl polystyrene); Polymer-bound oxidizingreagents (e.g., Polystyrylmethyl)trimethylammonium metaperiodate,(Polystyrylmethyl)trimethylammonium perruthenate,4-(Polystyrylmethyloxy)-2,2,6,6-tetramethyl-piperidin-1-yloxy freeradical, 6-(Methylsulfinyl)hexanoylmethyl polystyrene, TEMPOpolystyrene); Polymer-bound phosphines (e.g., Di(n-butyl)phenylphosphinepolystyrene, Di-o-tolyl-phenylphosphine polystyrene,Dicyclohexylphenylphosphine polystyrene, DiphenylphosphinobenzoylNovaGel™ AM resin, Diphenylphosphinomethyl polystyrene,Diphenylphosphinopolystyrene, Triphenylphosphine NovaGel™,Triphenylphosphine polystyrene); or Polymer-bound reducing agents (e.g.,(Polystyrylmethyl)trimethylammonium borohydride,(Polystyrylmethyl)trimethylammonium cyanoborohydride, Dimethylsilylpolystyrene).

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structure is tobe accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

4. DETAILED DESCRIPTION OF THE INVENTION

This invention is directed, in part, to novel methods of preparingsulfinamides and sulfoxides. These methods can be used, for example, toprovide sulfinamides such as, but not limited to, stereomerically pureforms of tert-butanesulfinamide, and sulfoxides such as, but not limitedto, stereomerically pure forms of compounds disclosed by U.S. Pat. No.5,776,765 (e.g., 2-(2-pyridylmethyl)sulfinyl)benzimidazoles) and U.S.Pat. No. 5,945,425 (e.g., (H⁺/K⁺)ATPase inhibitors), both of which areincorporated herein by reference.

A first embodiment of the invention encompasses a method of preparing asulfinamide or sulfoxide, which comprises contacting a compound ofFormula 1:

wherein n is 0 to 3; L is CO_(m)R₃ or SO_(m)R₃, wherein m is 0 to 3; R₁and R₂ together form a cyclic structure (e.g., substituted orunsubstituted heterocycle or aryl) or each of R₁ and R₂ is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle; R_(1′) andR_(2′) together form a cyclic structure or each of R_(1′) and R_(2′) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted aralkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheterocycle; R_(a) and R_(b) together form a cyclic structure or each ofR_(a) and R_(b) is independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; and each of R₃ and X isindependently a polymer bound alkyl, aryl or heteroalkyl, substituted orunsubstituted alkyl, substituted or unsubstituted aralkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted ether, substituted or unsubstituted ester,substituted or unsubstituted ketone, substituted or unsubstitutedphosphonate, substituted or unsubstituted phosphonic acid ester,substituted or unsubstituted phosphinoyl (e.g., —P(═O)(R₁)₃; wherein R₁is defined above), substituted or unsubstituted sulfide, substituted orunsubstituted sulfone, substituted or unsubstituted sulfinyl imine(e.g., —S(═O)(═NR₁)—R₂ wherein R₁ and R₂ are defined above), substitutedor unsubstituted heterocycle, or —NR₄R₅, wherein R₄ and R₅ together withthe nitrogen atom to which they are attached form a heterocycle or eachof R₄ and R₅ is independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, substituted orunsubstituted ether, substituted or unsubstituted sulfide, orsubstituted or unsubstituted heterocycle;

with a compound of the formula MY, wherein M is a metal or metal complexcapable of transferring Y to the positively charged sulfur atom of thecompound of Formula 1 and Y is independently substituted orunsubstituted alkyl, substituted or unsubstituted aralkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted ether, substituted or unsubstituted ester,substituted or unsubstituted ketone, substituted or unsubstitutedphosphonate, substituted or unsubstituted phosphonic acid ester,substituted or unsubstituted phosphinoyl, substituted or unsubstitutedsulfide, substituted or unsubstituted sulfone, substituted orunsubstituted sulfinyl imine, substituted or unsubstituted heterocycle,or is of the formula —NR₆R₇, wherein R₆ and R₇ together with thenitrogen atom to which they are attached form a heterocycle or each ofR₆ and R₇ is independently a polymer bound alkyl, aryl or heteroalkyl;hydrogen; substituted or unsubstituted alkyl; substituted orunsubstituted aralkyl; substituted or unsubstituted heteroalkyl;substituted or unsubstituted aryl; substituted or unsubstituted ether;substituted or unsubstituted ester; substituted or unsubstituted ketone;substituted or unsubstituted phosphonate; substituted or unsubstitutedphosphonic acid ester; substituted or unsubstituted phosphinoyl;substituted or unsubstituted sulfide; substituted or unsubstitutedsulfone; substituted or unsubstituted sulfinyl imine; substituted orunsubstituted heterocycle; under conditions suitable for the formationof a compound of Formula 2:

wherein X and Y are defined above.

In a preferred method of this embodiment, the compound(s) of Formula 1and/or Formula 2 is/are stereomerically pure.

In another preferred embodiment, the compounds of Formula 1 have thefollowing structures:

In another method of this embodiment, M of the formula MY is Al, Ba, Li,Na, K, Mg, Mn, Zn, Cd, In, or Cu; in another method, M is of the formulaCdZ, BaZ, MgZ, ZnZ, AlZ₂, MnZ, InZ, or CuZ, wherein Z is Cl, Br, I,aryl, aralkyl, or heterocycle.

In another method, the compound of Formula 1 is prepared by contacting acompound of Formula 3:

wherein n is 0 to 3; L is CO_(m)R₃or SO_(m)R₃, wherein m is 0 to 3; andR₁, R₂, R_(1′), R_(2′), and R₃ are defined above;

with a compound of the formula M′X, wherein M′ is a metal or metalcomplex capable of transferring X to the positively charged sulfur atomof the compound of Formula 3 and X is defined above.

In a preferred embodiment, the compounds of Formula 3 have the followingstructures:

In a preferred method of this embodiment, M′ of the formula M′X is Al,Ba, Li, Na, K, Mg, Mn, Zn, Cd, In, or Cu; in another method, M′ is ofthe formula CdZ′, BaZ′, MgZ′, ZnZ′, AlZ′₂, MnZ′, InZ′, or CuZ′, whereinZ′ is Cl, Br, I, aryl, aralkyl, or heterocycle or a combination with aLewis acid, such as, but not limited to, Ti(OPr)₄ or Ti(OR₁)₃Cl, whereR₁ is defined above.

In another preferred method of this embodiment, X is tert-butyl,trialkylmethyl, triheteroalkylmethyl, triarylmethyl,triheteroarylmethyl, triheterocyclemethyl, aryl, heterocyclic,heteroaryl, alkyltrialkyl, alkylheteroalkylmethyl, diarylalkylmethyl,adamantyl, dialkyladamantyl, trialkylaryl, triethylmethyl,dimethylethyl, trimethylphenyl, trialkylphenyl, triisopropylphenyl,polymer bound alkyl or aryl or is of Formula 4: or is of Formula 4:

or a salt thereof, wherein each R₈ is independently substituted orunsubstituted alkyl, substituted or unsubstituted aralkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted ether, substituted or unsubstitutedsulfide, substituted or unsubstituted heterocycle, a primary, secondary,or tertiary amine, or a halogen atom; and p is an integer of 0 to 4; oris of Formula 5:

wherein each R₉ is independently substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted aryl, substituted or unsubstitutedether, substituted or unsubstituted sulfide, substituted orunsubstituted heterocycle, a primary, secondary, or tertiary amine, or ahalogen atom; and q is an integer of 0 to 4. Preferably, q is 2 or 3.

If X is of Formula 4, p is preferably 0 or 1. If p is 1, R₈ ispreferably —OCH₃ or —OCHF₂. If X is of Formula 5 and q is 2, each R₉ ispreferably —CH₃, —OCH₃, —OCH₂CF₃, or —OC₅H₁₁; if q is 3, R₉ ispreferably —CH₃ or —OCH₃.

In another preferred method of this embodiment, Y is —NR₆R₇ or is ofFormula 4 or Formula 5. If Y is of Formula 4, p is preferably 0 or 1. Ifp is 1, R₈ is preferably —OCH₃ or —OCHF₂. If Y is of Formula 5 and q is2, each R₉ is preferably —CH₃, —OCH₃, —OCH₂CF₃, or —OC₅H₁₁; if q is 3,R₉ is preferably —CH₃ or —OCH₃.

In another preferred method of this embodiment, R₁ is aryl or aklyl. Ina more preferred method, R₁ is methyl.

In another preferred method of this embodiment, R₂ is aryl or alkyl. Ina more preferred method, R₂ is phenyl.

In another preferred method of this embodiment, R₃ is a substituted orunsubstituted heteroalkyl, substituted or unsubstituted lower alkyl(e.g., halogenated phenyl, 3-methylphenyl, 4-methylphenyl,1,3,5-trimethylphenyl, (tert-butyl)phenyl, 2-mesityl, tolyl, or1,3,5-triisopropylphenyl), or aryl (e.g., phenyl and biphenyl). In amore preferred method, R₃ is 2-mesityl, tolyl, tri-isopropyl, or apolymer bound aryl or alkyl.

In a preferred method of this embodiment, the compound of Formula 1 isstereomerically pure and has one of the following stereochemistries:

In another preferred method of this embodiment, the compound of Formula1 has one of the following structures:

wherein X and R₃ are each defined above and each R₁₀ is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted aryl, substituted or unsubstitutedether, substituted or unsubstituted sulfide, a primary, secondary, ortertiary amine, a heterocycle, or a halogen atom; n is an integer of 1to 4; and m is an integer of 0 to 4. In a preferred method, n is 1 and mis 0, 1, or 2, and wherein R₃ is tert-butyl, trialkylmethyl,triheteroalkylmethyl, triarylmethyl, triheteroarylmethyl,triheterocyclemethyl, aryl, heterocyclic, heteroaryl, alkyltrialkyl,alkylheteroalkylmethyl, diarylalkylmethyl, adamantyl, dialkyladamantyl,trialkylaryl, triethylmethyl, dimethylethyl, trimethylphenyl,trialkylphenyl, triisopropylphenyl, polymer bound alkyl or aryl or is ofFormula 4:

or a salt thereof, wherein each R₈ is independently substituted orunsubstituted alkyl, substituted or unsubstituted aralkyl, substitutedor unsubstituted aryl, substituted or unsubstituted ether, substitutedor unsubstituted sulfide, substituted or unsubstituted heterocycle, aprimary, secondary, or tertiary amine, or a halogen atom; and p is aninteger of 0 to 4; or is of Formula 5:

wherein each R₉ is independently substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,substituted or unsubstituted ether, substituted or unsubstitutedsulfide, substituted or unsubstituted heterocycle, a primary, secondary,or tertiary amine, or a halogen atom; and q is an integer of 0 to 4. Ina preferred method, the compound of Formula 6 or 7 is stereomericallypure.

In a preferred method of this embodiment, the compound of Formula 2 isof Formula 8, stereoisomers of which are shown below:

In a particularly preferred method of this embodiment, X is phenyl,4-methylphenyl, tert-butyl, adamantyl, trimethylphenyl, pyridyl, ortrialkylmethyl, triisopropylphenyl, trialkyl phenyl, tetraacylphenyl, orpentaalkylphenyl, triheteroalkylmethyl, triarylmethyl,triheteroarylmethyl, triheterocyclemethyl, aryl, heterocyclic,heteroaryl, alkyltrialkyl, alkylheteroalkylmethyl, diarylalkylmethyl,dialkyladamantyl, trialkylaryl, triethylmethyl, dimethylethyl,trialkylphenyl, triisopropylphenyl, polymer bound alkyl or aryl or is ofFormula 4:

or a salt thereof, wherein each R₈ is independently substituted orunsubstituted alkyl, substituted or unsubstituted aralkyl, substitutedor unsubstituted aryl, substituted or unsubstituted ether, substitutedor unsubstituted sulfide, substituted or unsubstituted heterocycle, aprimary, secondary, or tertiary amine, or a halogen atom; and p is aninteger of 0 to 4; or is of Formula 5:

wherein each R₉ is independently substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,substituted or unsubstituted ether, substituted or unsubstitutedsulfide, substituted or unsubstituted heterocycle, a primary, secondary,or tertiary amine, or a halogen atom; and q is an integer of 0 to 4. Inanother preferred method, at least one of R₆ and R₇ is hydrogen. In yetanother preferred method, R₆ and R₇ are both hydrogen.

In another preferred method of this embodiment, the compound of Formula3 has one of the following stereochemistries:

In a particularly preferred method of this embodiment, the compound ofFormula 3 has one of the following structures:

wherein R₃, R₁₀, m, and n are defined herein.

With regard to compound 10, when n is 1, the stereochemistry of thecompound is preferably cis, two isomers of which are shown below:

A specific method of this embodiment is a method of preparingpantoprazole, or a derivative, prodrug, salt, solvate, clathrate, orstereomerically pure form thereof, which comprises contacting a compoundof Formula 11:

wherein R₁, R₂, R_(1′), and R_(2′) are defined herein, and Prot is aprotecting group (e.g., an animal or sulfanamide), with a compound ofFormula 12:

wherein M is defined herein, under conditions suitable for the formationof a compound of Formula 13:

and optionally contacting the compound of Formula 13 with a reagentcapable of replacing Prot with a hydrogen atom or a cation (e.g., Na⁺ orK⁺). Suitable reagents include, but are not limited to NaOH, KOH, or amild acid followed by NaH or KH.

In a preferred method, the compound of Formula 11 is prepared bycontacting a compound of Formula 3 with a compound of Formula 14:

wherein M′ is defined herein, under conditions sufficient for theformation of the compound of Formula 11.

In another preferred method, the compounds of formulas 11 and 13 areenantiomerically pure.

Another specific method of this embodiment is a method of preparinglansoprazole, or a derivative, prodrug, salt, solvate, clathrate, orstereomerically pure form thereof, which comprises contacting a compoundof Formula 15:

wherein R₁, R₂, R_(1′), R_(2′), and Prot are defined herein, with acompound of Formula 16:

wherein M is defined herein, under conditions suitable for the formationof a compound of Formula 17:

and optionally contacting the compound of Formula 17 with a reagentcapable of replacing Prot with a hydrogen atom or a cation.

In a preferred method, the compound of Formula 15 is prepared bycontacting a compound of Formula 3 with a compound of Formula 18:

wherein M′ is defined herein, under conditions sufficient for theformation of the compound of Formula 15.

In another preferred method, the compounds of formulas 15 and 17 areenantiomerically pure.

Another specific method of this embodiment is a method of preparingomeprazole, or a derivative, prodrug, salt, solvate, clathrate, orstereomerically pure form thereof, which comprises contacting a compoundof Formula 19:

wherein R₁, R₂, R_(1′), R_(2′), and Prot are defined herein, with acompound of Formula 20:

wherein M is defined herein, under conditions suitable for the formationof a compound of Formula 21:

and optionally contacting the compound of Formula 21 with a reagentcapable of replacing Prot with a hydrogen atom or a cation.

In a preferred method, the compound of Formula 19 is prepared bycontacting a compound of Formula 3 with a compound of Formula 22:

wherein M′ is defined herein, under conditions sufficient for theformation of the compound of Formula 19.

In another preferred method, the compounds of formulas 19 and 21 areenantiomerically pure.

Still another specific method of this embodiment is a method ofpreparing rabeprazole, or a derivative, prodrug, salt, solvate,clathrate, or stereomerically pure form thereof, which comprisescontacting a compound of Formula 15:

wherein R₁, R₂, R_(1′), R_(2′), and Prot are defined herein, with acompound of Formula 23:

wherein M is defined herein, under conditions suitable for the formationof a compound of Formula 24:

and optionally contacting the compound of Formula 24 with a reagentcapable of replacing Prot with a hydrogen atom or a cation.

In a preferred method, the compound of Formula 15 is prepared bycontacting a compound of Formula 3 with a compound of Formula 18:

wherein M′ is defined herein, under conditions sufficient for theformation of the compound of Formula 23.

In another preferred method, the compounds of formulas 23 and 25 areenantiomerically pure.

A second embodiment of the invention encompasses various compounds thatare particularly useful for the preparation of sulfinamides andsulfoxides. For example, the invention encompasses compounds of Formula7:

and salts, solvates, clathrates, and stereomerically pure forms thereof,wherein R₃ is independently substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,substituted or unsubstituted ether, substituted or unsubstitutedsulfide, substituted or unsubstituted heterocycle, or —NR₄R₅, wherein R₄and R₅ together with the nitrogen atom to which they are attached form aheterocycle or each of R₄ and R₅ is independently hydrogen, isindependently substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, substituted orunsubstituted ether, substituted or unsubstituted sulfide, orsubstituted or unsubstituted heterocycle; each R₁₀ is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted aryl, substituted or unsubstitutedether, substituted or unsubstituted sulfide, a primary, secondary, ortertiary amine, a heterocycle, or a halogen atom; n is an integer of 1to 4; and m is an integer of 0 to 4.

In preferred compounds of Formula 7, R₃ is a substituted orunsubstituted lower alkyl, substituted or unsubstituted aralkyl (e.g.,halogenated phenyl, 3-methylphenyl, 2-methylphenyl, 2-mesityl, tolyl,4-(tert-butyl)phenyl, or 2,4,6-triisopropylphenyl), or aryl (e.g.,phenyl and biphenyl). In more preferred compounds, R₃ is 2-mesityl ortolyl.

In other preferred compounds of Formula 7, each R₁₀ is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, or substituted or unsubstituted aryl. In more preferredcompounds of Formula 7, each R₁₀ is independently alkyl, aralkyl, oraryl.

In preferred compounds of Formula 7, n is 1 and m is 0, 1, or 2.

Preferred compounds of Formula 7 are stereomerically pure.

The invention further encompasses compounds of Formula 25:

and salts, solvates, clathrates, and stereomerically pure forms thereof,wherein R₁ and R₂ together form a cyclic structure (e.g., substituted orunsubstituted heterocycle or aryl) or each of R₁ and R₂ is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heterocycle; R₃ is substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,substituted or unsubstituted ether, substituted or unsubstitutedsulfide, substituted or unsubstituted heterocycle, or —NR₄R₅, wherein R₄and R₅ together with the nitrogen atom to which they are attached form aheterocycle or each of R₄ and R₅ is independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted aralkyl,substituted or unsubstituted aryl, substituted or unsubstituted ether,substituted or unsubstituted sulfide, or substituted or unsubstitutedheterocycle; each R₁₁ is independently substituted or unsubstitutedalkyl, substituted or unsubstituted aralkyl, substituted orunsubstituted aryl, substituted or unsubstituted ether, substituted orunsubstituted sulfide, a primary, secondary, or tertiary amine, aheterocycle, or a halogen atom; R₁₂ is substituted or unsubstitutedalkyl, substituted or unsubstituted aralkyl, substituted orunsubstituted aryl, substituted or unsubstituted ether, substituted orunsubstituted sulfide, or substituted or unsubstituted heterocycle, oris a sulfoxide; and r is an integer from 0 to 4.

In preferred compounds of Formula 25, n is 1, m is 0, 1, or 2, and r is2 or 3.

In additional preferred compounds of Formula 25, R₁ is phenyl or loweralkyl. In a particular compound, R₁ is methyl.

In additional preferred compounds of Formula 25, R₂ is phenyl or loweralkyl. In a particular compound, R₂ is phenyl.

In additional preferred compounds of Formula 25, R₃ is a substituted orunsubstituted lower alkyl, substituted or unsubstituted aralkyl (e.g.,halogenated phenyl, 3-methylphenyl, 4-methylphenyl,1,3,5-trimethylphenyl, (tert-butyl)phenyl, 2-mesityl, tolyl, or1,3,5-triisopropylphenyl), or aryl (e.g., phenyl and biphenyl). In aparticular compound, R₃ is 2-mesityl or tolyl.

Specific preferred compounds of Formula 25 are those of Formula 26:

and salts, solvates, clathrates, and stereomerically pure forms thereof,wherein each R₁₁ is independently substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,substituted or unsubstituted ether, substituted or unsubstitutedsulfide, a primary, secondary, or tertiary amine, a heterocycle, or ahalogen atom; R₁₂ is substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, substituted orunsubstituted ether, substituted or unsubstituted sulfide, orsubstituted or unsubstituted heterocycle, or is a sulfoxide; and r is aninteger from 0 to 4.

In preferred compounds of Formula 26, R₁₂ is a protecting group.

In preferred compounds of Formula 26, each R₁₁ is independentlysubstituted or unsubstituted alkyl or substituted or unsubstitutedether.

In preferred compounds of Formula 26, n is 1, m is 0, 1, or 2, and r is2 or 3.

The invention further encompasses compounds of Formula 9:

and salts, solvates, clathrates, and stereomerically pure forms thereof,wherein R₃ is substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, substituted orunsubstituted ether, substituted or unsubstituted sulfide, substitutedor unsubstituted heterocycle, polymer bound alkyl or aryl, or —NR₄R₅,wherein R₄ and R₅ together with the nitrogen atom to which they areattached form a heterocycle or each of R₄ and R₅ is independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, substituted orunsubstituted ether, substituted or unsubstituted sulfide, orsubstituted or unsubstituted heterocycle.

In preferred compounds of Formula 9, R₃ is a substituted orunsubstituted lower alkyl, substituted or unsubstituted aralkyl (e.g.,halogenated phenyl, 3-methylphenyl, 2-methylphenyl, 2-mesityl, tolyl,4-(tert-butyl)phenyl, or 2,4,6-triisopropylphenyl), or aryl (e.g.,phenyl and biphenyl). In more preferred compounds, R₃ is 2-mesityl ortolyl.

Preferred compounds of Formula 9 are stereomerically pure.

The invention further encompasses compounds of Formula 10:

and salts, solvates, clathrates, and stereomerically pure forms thereof,wherein R₃ is substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, substituted orunsubstituted ether, substituted or unsubstituted sulfide, substitutedor unsubstituted heterocycle, polymer bound alkyl or aryl, or —NR₄R₅,wherein R₄ and R₅ together with the nitrogen atom to which they areattached form a heterocycle or each of R₄ and R₅ is independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, substituted orunsubstituted ether, substituted or unsubstituted sulfide, orsubstituted or unsubstituted heterocycle; each R₁₀ is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted aryl, a primary, secondary, ortertiary amine, or a halogen atom; n is an integer of 1 to 4; and m isan integer of 0 to 4.

In preferred compounds of Formula 10, R₃ is a substituted orunsubstituted lower alkyl, substituted or unsubstituted aralkyl (e.g.,halogenated phenyl, 3-methylphenyl, 2-methylphenyl, 2-mesityl, tolyl,4-(tert-butyl)phenyl, or 2,4,6-triisopropylphenyl), or aryl (e.g.,phenyl and biphenyl). In more preferred compounds, R₃ is 2-mesityl ortolyl.

In other preferred compounds of Formula 10, n is 1 and m is 0, 1, or 2.

Preferred compounds of Formula 10 are stereomerically pure.

Also encompassed by the invention are compounds oil Formula 56:

and salts, solvates, clathrates, and stereomerically pure forms thereof,wherein R₃ is substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, substituted orunsubstituted ether, substituted or unsubstituted sulfide, substitutedor unsubstituted heterocycle, polymer bound alkyl or aryl, or —NR₄R₅,wherein R₄ and R₅ together with the nitrogen atom to which they areattached form a heterocycle or each of R₄ and R₅ is independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, substituted orunsubstituted ether, substituted or unsubstituted sulfide, orsubstituted or unsubstituted heterocycle.

In preferred compounds of Formula 56, R₃ is a substituted orunsubstituted lower alkyl, substituted or unsubstituted aralkyl (e.g.,halogenated phenyl, 3-methylphenyl, 2-methylphenyl, 2-mesityl, tolyl,4-(tert-butyl)phenyl, or 2,4,6-triisopropylphenyl), or aryl (e.g.,phenyl and biphenyl). In more preferred compounds, R₃ is 2-mesityl ortolyl.

Preferred compounds of Formula 56 are stereomerically pure.

4.1. PREPARATION OF SULFINAMIDES AND SULFOXIDES

In general, sulfinamides and sulfoxides are prepared according to thisinvention by contacting a compound of Formula 1:

wherein R₁, R_(1′), R₂, R_(2′), R₃, and X are defined herein, with areagent that will cleave the sulfur-oxygen bond to provide a compound ofFormula 2:

In preferred methods of the invention, the compounds of formulas 1 and 2are stereomerically pure.

A particular method of the invention is shown below in Scheme II:

As shown in Scheme II, a compound of Formula 27 is contacted with acompound of the formula HalSO₂R₃, wherein Hal is halogen and R₁, R₂, andR₃ are defined herein, under conditions suitable for the formation of acompound of Formula 28. Examples of HalSO₂R₃ include, but are notlimited to, p-toluenesulfonyl chloride and mesitylsulfonyl chloride. Asthose of skill in the art will recognize, the particular conditionssufficient for this reaction to occur will depend on the specificcompounds being reacted. Suitable conditions will be readily apparent tothe skilled chemist. In one example, triethylamine is used with asolvent such as, but not limited to, methylene chloride.

The compound of Formula 28 is then contacted with a reagent capable offorming a five-membered ring to provide compound 3. One example of sucha reagent is SOCl₂ with a base in a suitable solvent. Examples of basesinclude, but are not limited to, trialkylamines (e.g., triethylamine),pyridine, imidazole, quinoline, and derivatives thereof. Examples ofsuitable solvents include, but are not limited to, THF, methyl-THF,CH₂Cl₂, ClCH₂CH₂Cl, toluene, chlorobenzene, dichlorobenzene, dioxanes,MTBE/THF, DME, and other solvent mixtures. Another example of a reagentthat can be used to form the compound of Formula 3 is 2,4,6-collidine ora substituted pyridine or pyridine analogue in a solvent such as, butnot limited to, THF.

The effects of various reagents and reaction conditions on the formationand stereochemistry of specific compounds of Formula 3 shown below, areprovided in Table 1:

TABLE 1

R₁₀′ Endo:Exo (solvent and at −45° C. unless R₃ R₁₀″ n Base otherwiseindicated) 4-methylphenyl H 1 Triethylamine 75:25 (THF) ″ ″ 1Triethylamine 62:38 (THF/CH₂Cl₂ 1:1) ″ ″ 1 Triethylamine 87:13 (CH₃CN) ″″ 1 Triethylamine 73:27 (EtOAc) ″ ″ 1 Imidazole 70:30 (THF) ″ ″ 11-Methylimidazole 75:25 (THF) ″ ″ 1 Pyridine 75:25 (THF) ″ ″ 12,6-Lutidine 85:15 (THF) ″ ″ 1 2,4,6-Collidine 91:9 (THF) ″ ″ 12,6-Di-t- 3:97 (THF) Butylpyridine ″ ″ 1 4-Me-2,6-t-Bu- 20:80 pyridine(THF) (−20° C.) ″ ″ 1 4-t-Butylpyridiene 84.3:15.7 (THF) ″ ″ 1 2,6-15.8:84.2 Dimethoxypyridine (CH₂Cl₂, 0° C.) ″ ″ 1 Quinaldine 87:13 (THF)″ ″ 1 Lepidine 88:12 (THF) ″ CH₃ 1 Pyridine 97:3 (THF) ″ H 2 Pyridine97:3 (THF) ″ ″ 1 4-Picoline 78:22 (THF) 2-mesityl H 1 Triethylamine85:15 (THF) ″ ″ 1 Triisopropylamine 66.7:33.3 (THF) ″ ″ 1 Diethylaniline2:98 (CH₂Cl₂, −15° C.) ″ ″ 1 Diethylaniline 37:63 (THF, −20° C.) ″ ″ 1Triphenyamine No reaction ″ ″ 1 Imidazole 82:18 (THF) ″ ″ 12-Methylimidazole 85.7:14.3 (THF) ″ ″ 1 2-Ethylimidazole 66:33 ″ ″ 1Pyridine 90:10 (THF) ″ ″ 1 2-Phenylpyridine 83:17 (THF) ″ ″ 12,4,6-Collidine 93:7 (THF) ″ ″ 1 2,6- 2:98 Dimethoxypyridine (CH₂Cl₂,−15° C.) ″ ″ 1 2,6- 75:25 Dimethoxypyridine (THF, −45° C. - r.t) ″ ″ 1Lepidine 94:6 (THF) 2,4,6-triisopropyl H 1 Triethylamine 87:13 (THF)phenyl ″ ″ 1 2,4,6-Collidine 95:5 (THF) 4-t-butylphenyl H 1Triethylamine 80:20 (THF) ″ ″ 1 Triethylamine 40:60 (CH₂Cl₂)4-methylphenyl CH₃ 1 Triethylamine 85.7:14.3 (CH₂Cl₂)

As shown in Scheme II, the ring of compound 3 is selectively opened bycontacting it with an organometallic reagent to provide a compound ofFormula 1. Examples of organometallic reagents include, but are notlimited to, those of the formula M′X, wherein M′ of the formula M′X isAl, Ba, Li, Na, K, Mg, Mn, Zn, Cd, In, Cu or is of the formula CdZ′,BaZ′, MgZ′, ZnZ′, AlZ′₂, MnZ′, InZ′, CuZ′, Ti(OR₁)₃Z′, or Ti(OR₁)₄wherein Z′ is Cl, Br, I, aryl, aralkyl, or heterocycle, wherein R₁ isdefined herein.

The sulfur-oxygen bond of the compound of Formula 1 is then cleaved bycontacting it with a compound of formula MY to provide the desiredsulfinamide or sulfoxide of Formula 2. MY can be the same or differentfrom MZ: M is a metal such as Al, Ba, Li, Na, K, Mg, Mn, Zn, Cd, In, Cuor is of the formula CdZ, BaZ, MgZ, ZnZ, AlZ₂, MnZ, InZ, or CuZ,Ti(OR₁)₃Z, or Ti(OR₁)₄ wherein Z is Cl, Br, I, aryl, aralkyl, orheterocycle, wherein R₁ is defined herein.

Depending on the actual compound of formula MY, this final reaction ofScheme II can provide a variety of different sulfoxides andsulfinamides, and stereomerically pure sulfoxides and sulfinamides inparticular. For example, when MY is NH₂Li/NH₃, this method can be usedto provide stereomerically pure alkyl (e.g., tert-butyl), aryl (e.g.,tolyl), heteroalkyl (e.g., tert-butyl amino), heterocyclic(e.g.,tetrahydrofuryl , or heteroaryl (e.g., pyridyl) sulfinamide.

Specific methods of the invention, which can be used to prepareenantiomerically pure pantoprazole, lansoprazole, omeprazole, andrabeprazole, and pharmaceutically acceptable salts, solvates,clathrates, hydrates, prodrugs, and stereomerically pure forms thereof,are represented below in schemes III-VI, respectively. In each scheme,the stereochemistry of the compound of Formula 3 is different in orderto emphasize that the stereochemistry of the final product can be variedby simply altering the corresponding stereochemistry of the startingmaterial. As with all schemes disclosed herein, those shown below areprovided by way of illustration, and are not to be construed as limitingthe scope of the invention.

In each of schemes III-VI, M and M′ are as defined herein, and Prot is aprotecting group. Suitable protecting groups are known in the art andinclude, but are not limited to, —CH₂OCH₃, —CH₂OCH₂OCH₃, alkyl sulfonyl,and aryl sulfonyl.

The reagents used in each of these schemes are commercially available orreadily prepared. For example, the benzimidazole metal conjugates usedin the first step of each of schemes III-VI (i.e., compounds 14, 18, 22and 18) can be prepared by methods known in the art. See, e.g., Abarbri,M., et al., Tetrahedron Lett. (1999) 40:7449-7453 and Abarbri, M., etal., J. Org. Chem. (2000) 65:4618-4634. The synthesis of protectedbenzimidazoles is also well known. See, e.g., Sih, J. C. et al., J. Med.Chem. (1991) 34:1049-1062 and Singh, M. P., et al., Heterocycles (1993)36:971-985. The pyridinyl metal conjugates used in the second step ofcach of the schemes (i.e., compounds 12, 16, 20, and 23) are alsoreadily prepared using well-known methods. See, e.g., Baldenius, K.-U.and Kagan, H. B., Tetrahedron: Asym. (1990) 1:597-610.

5. EXAMPLES

Certain embodiments of the invention are illustrated by the followingnon-limiting examples.

5.1. Example 1 Asymmetric Synthesis of a Sulfinamide via1,2,3-oxathiazolidine-s-oxide

Examples of the general approach shown in Scheme II are described below,and can be understood with reference to Schemes VII-XII:

Preparation of (1R, 2S)-1-amino-2-indanol-N-2,4,6-mesitylsulfonamide(31): To a 2 L mL three neck round-bottomed flask equipped with anoverhead stirrer and temperature probe, was charged NaHCO₃ (42.2 g, 502mmol), followed by 200 mL of water and the mixture was stirred for 15min. EtOAc (500 mL), THF (100 mL), and aminoindanol (30) (50 g, 336mmol) were added and the slurry was mixed for 5 minutes.2-Mesitylenesulfonyl chloride (70.4 g, 322 mmol) was added in oneportion, the reaction mixture was stirred vigorously for 5-6 hours, andthe reaction was monitored by TLC for the disappearance of2-mesitylenesulfonyl chloride. Stirring was stopped and the phases wereallowed to separate. The organic phase was washed with water (200 mL),1.5 M HCl (75 mL) and water (200 mL). Evaporation of the organic solventto dryness provided a solid product which was treated with heptane (400mL) and the mixture was stirred for 2 hours. The resulting slurry wasfiltered and the wet cake dried under reduced pressure to give 104 g(93%) of the title product. ¹H NMR (300 MHz, CDCl₃): δ 2.30 (s, 3H),2.68 (s, 6H), 2.81-3.04 (m, 3H), 4.22-4.32 (m, 1H), 4.48-4.58 (m, 1H),5.58-5.61 (d, J=9.5 Hz, 1H) 6.95-7.24 (m, 6H). ¹³C NMR (CDCl₃): δ 21.3,23.3, 39.6, 61.3, 73.2, 124.9, 125.6, 127.4, 128.7, 132.3, 134.1, 139.7,139.8, 140.0, and 142.8. Alal. Calcd for C₁₈H₂₁NO₃S: C, 65.23; H, 6.39;N, 4.23; O, 14.48; 5, 9.68. Found: C, 65.36; H, 6.40; N, 4.08; S, 9.70.

Preparation of(2R,4R,5S)-3-(2,4,6-mesitylsulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2-oxide (32) from (1R, 2S)-aminoindanol mesitylene sulfonamide (31): Toa 1 L three-necked flask equipped with a mechanical stirrer, an argoninlet, a thermometer probe and rubber septum, was charged (1R,2S)-aminoindanol mesitylene sulfonamide (31 g, 93.7 mmol), THF (50 mL)and the reaction mixture was cooled to −45° C. Thionyl chloride (15.2 g,128 mmol) was added slowly via syringe in one portion, followed by slowaddition of collidine (32 g, 264 mmol) in THF (250 mL) for 6 hours. Thereaction was quenched with aqueous NaHCO₃ (100 mL), diluted with EtOAc(100 mL) and warmed to room temperature. The organic layer was washedwith brine (100 mL), dried with Na₂SO₄ and concentrated to dryness. Theresidue was added heptane (150 mL), stirred for 2 hours, and filtered togive a white or off white solid product with 85% de. Crystallizationfrom EtOAc/heptane provided a white solid product. The mother liquor wasconcentrated, and a second crop of crystals was obtained. This processwas repeated two times to give a total yield of 28 g (78%) of(2R,4R,5S)-3-(2,4,6-mesitylsulfonyl)-3,3a,8,8a-tetrahydro-1-oza-2-thia-3-aza-cyclopenta[a]indene2-oxide (32) with >99% de.

Preparation of(2S,4S,5R)-3-(2,4,6-mesitylsulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2-oxide (36) from (1S, 2R)-1-amino-2-indanol-N-2,4,6-mesitylsufonamide(35): The same procedure described above was used to provide the productwith 76% yield and >99% de. ¹H NMR (CDCl₃): δ 2.41 (s, 3H), 2.77 (s,6H), 3.40-3.66 (m, 2H), 5.57 (d, J=6.4 Hz, 1H), 5.86-5.91 (m, 1H), 6.63(d, J=8.1 Hz, 1H), 7.08-7.34 (m, 5H). ¹³C NMR (CDCl₃): δ 21.5, 23.4,39.6, 66.6, 96.0, 125.0, 125.8, 128.1, 129.8, 132.8, 138.8, 141.2,145.1. Anal. C₁₈H₁₉NO₄S₂, Cal: C, 57.27; H, 5.07; N, 3.71; S, 16.99.Found: C, 57.45; H, 5.14; N, 3.76; S, 16.93.

Preparation of aminoindanol 4-toluene sulfonamide(1R,2R,3S)-1,2,3-oxathiazolidine-S-oxide (39) from (1R,2S)-1-amino-2-indanol-N-4-toluenesulfonamide (38) or aminoindanol4-toluene sulfonamide (1S, 2S, 3R)-1,2,3-oxathiazolidine-S-oxide (42)from (1S,2R)-1-amino-2-indanol-N-4-toluenesulfonamide (41): The sameprocedure described above was used to provide the title compoundquantitatively with 82% de. Crystallization from heptane/EtOAc furnishedthe diastereomeric pure product with >99% de (minor diastereomere notdetected) and 65% yield. ¹H NMR(CDCl₃): δ 2.51 (s, 3H), 3.32-3.62 (m,2H), 5.38-5.52 (m, 2H), 7.81-7.89 (m, 6H), 7.81-7.89 (m, 2H). ¹³C MNR(CDCl₃): δ 22.0, 39.7, 67.1, 93.3, 125.6, 126.0, 127.8, 128.1, 130.0,130.6, 135.9, 138.2, 138.6, 145.6. Anal: C₁₆H₁₅N₄S₂, Cal: C, 55.00; H,4.33; N, 4.01; S, 18.35. Found: C, 55.09; H, 4.37; N, 3.92; S, 18.39.

Preparation of(2S,4R,5S)-3-(4-toluenesulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2-oxide (44) from (1R, 2S)-1-amino-2-indanol-N-4-toluenesulfonamide(38): A 250 mL three-necked flask equipped with a mechanical stirrer, anargon inlet, a thermometer probe and rubber septum, was charged (1R,2S)-1-amino-2-indanol-N-4-toluenesulfonamide (10.0 g, 33.0 mmol), THF(30 mL) and the reaction mixture was cooled to −45° C. Thionyl chloride(5.9 g, 49.6 mmol) was added slowly via syringe in one portion, followedby slow addition of 2,6-di-t-butyl pyridine (15.8 g, 80.0 mmol) in THF(100 mL) for 1-2 hours, and the reaction mixture was allowed to warm toroom temperature with stirring. After 6-8 hours, as monitored by TLC fordisappearance of starting material, the reaction mixture was cooled to−5° C. and quenched with aqueous NaHCO₃ (40 mL), diluted with EtOAc (100mL) and warmed to room temperature. The organic layer was washed withbrine (100 mL) and concentrated to dryness. The residue was addedheptane (100 mL), stirred for 2 hours, and filtered to give a white oroff white solid product (11.0 g, 95.5%) with >97% de (the crude productwas used directly in the next step). Crystallization from EtOAc/heptanefurnished diastereomeric pure product (>99% de, minor diastereomer notdetected).

Preparation of(2R,4S,5R)-3-(4-toluenesulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2-oxide (46) from (1S,2R)-1-amino-2-indanol-N-4-toluenesulfonamide (41):The same procedure described above was used to provide the title productwith same result. ¹H NMR (CDCl₃): δ 2.46 (s, 3H), 3.31 (s, 2H),5.02-5.04 (d, J=5.0 Hz, 1H), 5.77-5.82 (m, 1H), 7.22-7.42 (m, 5H),7.96-8.04 (m, 3H). ¹³C NMR(CDCl₃): δ 22.0, 36.2, 65.1, 90.6, 125.2,127.0, 128.9, 129.8, 130.2, 135.5, 137.9, 139.2, 145.5. Anal C₁₆H₁₅NO₄S₂Cal: C, 55.0; H, 4.33; N, 4.01; S, 18.35. Found: C, 55.11; H, 4.35; N,4.00; S, 18.4.

Preparation of (S)-2-Methyl-2-propylsulfinic acid(1R,2S)-1-(2,4,6-mesitylsulfonylamino)-indan-2-yl ester (33) from(2R,4R,5S)-3-(2,4,6-mesitylsulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2oxide (32): In a 100 mL two-necked, round-bottomed flask equipped witha magnetic stir bar, rubber septum, and argon inlet was placed(2R,4R,5S)-3-(2,4,6-mesitylsulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2-oxide (32) (2.2 g, 5.8 mmol) dissolved in THF (20 mL) and the mixturewas cooled to −10° C. A solution of t-butyl magnesium chloride (10.8 mL,1.0 M) in THF was added dropwise via syringe for 1 hour and the reactionwas allowed to warm to room temperature with stirring. After 2 hours, asmonitored by TLC for the disappearance of the starting material, thereaction mixture was cooled to 0° C. quenched with aqueous NaHCO₃ (10mL), and diluted with EtOAc (20 mL). The aqueous phase was extractedwith EtOAc (10 mL). The combined organic phases were washed with brine(20 mL), dried with Na₂SO₄ and concentrated to afford a crystallineproduct (2.45 g, 96.5%) with >99% de (minor diastereomer not detected).

Preparation of (R)-2-Methyl-2-propylsulfinic acid(1S,2R)-1-(2,4,6-mesltylsulfonylamino)-indan-2-yl ester (37) from(2S,4S,5R)-3-(2,4,6-mesitylsulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2-oxide (36): The same procedure described above was used. The resultprovided 95% yield and >99% de. ¹H NMR(CDCl₃): δ 1.07 (s, 9H), 2.32 (s,3H), 2.71 (s, 6H), 3.06 (s, 2H), 4.75-4.85 (m, 2H), 5.64 (d, J=9.3 Hz,1H), 6.99 (s, 1H), 7.17-7.28 (m, 5H). ¹³C NMR (CDCl₃): δ 21.1, 21.8,37.8, 58.1, 60.5, 82.7, 124.8, 124.9, 127.8, 128.5, 132.3, 134.6, 137.8,139.6, 140.3, 142.6. Anal. C₂₂H₂₉NO₄S₂: Cal. C, 60.66; H, 6.71; N, 3.22;S, 14.72. Found: C, 60.75; H, 6.72; N, 3.15; S, 14.65.

Preparation of (S)-2-Methyl-2-propylsulfinic acid(1R,2S)-1-(4-toluenesulfonyl-amino)-indan-2-yl ester (40) from(2R,4R,5S)-3-(4-toluenesulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2-oxide (39) and (R)-tert-butyl (1S, 2R) aminoindanol 4-toluenesulfonamide sulfinate (43) from aminoindanol 4-toluene sulfonamide (1S,2S, 3R)-1,2,3-oxathiazolidine-S-oxide (42): The same procedure describedabove was used to provide the title product with 96% yield and >99% de.¹H NMR (CDCl₃): δ 1.12 (s, 9H), 2.48 (s, 3H), 2.95-3.14 (m, 2H),4.64-4.70 (m, 1H), 4.76-4.84 (m, 1H), 5.76 (d, 9.2 Hz, 1H), 7.16-7.50(m, 6H), 7.94-7.97 (m, 2H). ¹³C NMR (CDCl₃): δ 21.7, 38.0, 58.2, 60.6,83.1, 124.9, 124.995, 127.8, 128.6, 130.0, 137.5, 140.1, 143.8. Anal:C₂₀H₂₅NO₄S₂. Cal: C, 58.94; H, 6.18; N, 3.44; S, 15.74. Found: C, 59.10;H, 6.22; N, 3.35; S, 15.79.

Preparation of (R)-2-Methyl-2-propylsulfinic acid(1R,2S)-1-(4-toluenesulfonylamino)-indan-2-yl ester (45) from(2S,4R,5S)-3-(4-toluenesulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2-oxide (44): In a 100 mL two-necked, round-bottomed flask equipped witha magnetic stir bar, rubber septum, and argon inlet wasplaced(2S,4R,5S)-3-(4-toluenesulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2-oxide (4.5 g, 12.9 mmol) dissolved in THF (30 mL) and the mixture wascooled to 0° C. A solution of t-butyl magnesium chloride (25 mL, 1.0 M)in THF was added dropwise via syringe for 30 minutes with stirring.After 3-4 hours, as monitored by TLC for the disappearance of thestarting material, the reaction was quenched with aqueous NaHCO₃ (20mL), and diluted with EtOAc (50 mL). The aqueous phase was extractedwith EtOAc (20 mL) and the combined organic phases were washed withbrine (40 mL), dried with Na₂SO₄ and concentrated to afford acrystalline product (5.0 g, 95%) with >99% de (minor diastereomer notdetected). ¹H NMR (CDCl₃): δ 1.12 (s, 9H), 2.45 (s, 3H), 3.08-3.26 (m,2H), 4.84-4.88 (m, 1H), 4.94-4.97 (m, 1H), 5.32 (d, J=10.1 Hz),7.06-7.35 (m, 6H), 7.83-7.86 (m, 2H). ¹³C NMR (CDCl₃): δ 21.7, 21.9,38.6, 58.3, 60.8, 81.8, 124.1, 125.2, 127.3, 127.5, 128.9, 130.0, 138.1,138.5, 139.2, 143.9.

Preparation of (S)-t-butyl (1R, 2S) aminoindanol mesitylene sulfonamidesulfinate (33) (one pot procedure): A 50 mL three-necked flask equippedwith a mechanical stirrer, an argon inlet, a thermometer probe andrubber septum, was charged (1R,2S)-aminoindanol mesitylene sulfonamide(1.22 g, 3.2 mmol), THF (3 mL) and the reaction mixture was cooled to−45° C. Thionyl chloride (0.58 g, 4.9 mmol) was added slowly via syringein one portion, followed by slow addition of collidine (1.19 g, 9.8mmol) in THF (10 mL) for 3-4 hours, and the reaction was monitored byTLC. The reaction mixture was warmed to −5° C. -10° C. and stirred for 5min. The collidine-HCl salt was filtered and the cake washed with THF (4mL). The filtrate was cooled to −78° C. and tBuMgCl (6.4 mL, 1.0 M) inTHF was added slowly. After 4-5 hours, as monitored by TLC for thedisappearance of the starting material, aqueous NaHCO₃ (10 mL) was addedto quench the reaction, diluted with EtOAc (15 mL) and the mixture wasallowed to warm to room temperature The organic phase was washed withbrine, 10% NaCl and dried (Na₂SO₄). Removal of the solvent afforded aviscous oil that was added EtOAc (3 mL) and heptane (10 mL) and stirredfor 30 minutes. The crystalline precipitate formed was filtered andwashed with heptane and dried to afford the title compound (1.2 g, 75%)with >95% de. (The de was measured by ¹H NMR). ¹H NMR (CDCl₃): δ 1.40(s, 9H), 2.34 (s, 3H), 2.74 (s, 6H), 3.06-3.08 (s, 2H), 4.77-4.90 (m,2H), 5.65 (d, J=10 Hz), 7.02 (s, 1H), 7.27-7.37 (m, 5H). ¹³C NMR(CDCl₃): δ 21.2, 21.8 37.8, 58.1, 60.5, 82.7, 124.8, 124.9, 127.8,128.5, 132.3, 134.6, 137.6, 139.6, 140.5, 142.6.

Preparation of (R)-t-butylsulfinamide (8(R): LR)-TBSA) from(S)-tert-Butyl (1R, 2S)-aminoindanol mesitylene sulfonamide sulfinate(33): A 250 mL three-necked round-bottomed flask equipped with amechanical stirrer and an ammonia condenser at about −78° C. was chargedwith 50 mL of liquid ammonia under Ar atmosphere. After the addition ofa few crystals of Fe(NO₃)₃, lithium wire (0.25 g, 35 mmol) was addedportion-wise in a controlled manner and the internal temperature waskept around −45° C. When all the lithium was added and a gray suspensionwas formed, the reaction mixture was cooled to −78° C. and a solution of(S)-t-butyl (1R, 2S)-aminoindanol mesitylene sulfonamide sulfinate ester(5 g, 11.5 mmol) in THF (15 mL) was added slowly over a course of 45min. Once the addition was complete, the mixture was stirred foradditional 30-45 min. before NH₄Cl (2.8 g) was added. The cold bath wasremoved, and stirring continued until the mixture reached ambienttemperature. The remaining volatile material was removed under reducedpressure. To the remaining residue was added 5 mL water and stirred.EtOAc (50 mL) was added to the mixture and stirred. After separation ofthe phases, the organic phase was washed with brine (5 mL×2). Afterremoval of the organic solvent, the residue was added water (40 mL) andstirred for 1 hour. The slurry was filtered and the wet cake was washedwith water (10 mL). The aqueous filtrate was then saturated with NaCland extracted with EtOAc (20 mL×3). Removal of the organic solventafforded (R)-t-butylsulfinamide (0.75 g, 70%) with 97% ee. (HPLC,Chiralpak AS column, 90:10 hexane/ethanol; 1.2 mL/min, 222 nm; (R)-TBSAr_(t)=6.6 min.; (S)-TBSA, r_(t)=9.4 min.). ¹H NMR (CDCl₃): δ 1.18 (s,9H), 3.82 (br, s, 2H). ¹³C NMR(CDCIJ): δ 22.1, 55.3.

Preparation of (R)-2-Methyl-2-propylsulfinic acid(1S,2R)-1-(2,4,6-mesitylsulfonylamino)-indan-2-yl ester (37) or from(R)-2-Methyl-2-propylsulfinic acid(1R,2S)-1-(4-toluenesulfonylamino)-indan-2-yl ester (45): The sameprocedure described above was used to provide the title products with98% ee and 73% yield or 98% ee and 72% yield, respectively.

5.2. Example 2 Sulfanamide Synthesis via (1S,2R)-1-(n-mesitylenesulfonyl)amino-1-phenyl-2-propanol

One method of preparing sulfinamides is represented by Scheme XIII,below:

Preparation of (1S,2R)-N-(2-hydroxy-1-phenyl-propyl)-2,4,6-mesitylsulfonamide (49): (1S,2R)-1-amino-1-phenyl-2-propanol (48) (2.0 g, 10.6 mmol) was charged intoa 100 mL three neck round-bottomed flask equipped with an overheadstirrer and temperature probe, followed by methylene chloride (20 mL)and the mixture was cooled to 0° C. and stirred for 15 minutes.2-Mesitylenesulfonyl chloride (2.2 g, 10.1 mmol) was added in oneportion and the slurry was mixed for 5 minutes. Triethylamine (2.7 g,26.7 mmol) was added in 2 hours with stirring and the reaction wasmonitored by TLC for the disappearance of 2-mesitylenesulfonyl chloride.The reaction was quenched with saturated aqueous NaHCO₃ (20 mL) anddiluted with EtOAc (20 mL). The organic phase was washed with water (20mL), 1.0 M HCl (10 mL), water (20 mL) and dried over NaSO₄. Evaporationof the organic solvent to dryness provided the title product in 95%yield (3.3 g). ¹H NMR (CDCl₃): δ 1.02 (d, J=6.35 Hz, 3H), 2.14 (d,J=5.49 Hz, 1H), 2.21 (s, 3H), 2.49 (s, 6H), 4.07-4.11 (m, 1H), 4.15-4.18(m, 1H), 5.70 (d, J=7.21 Hz, 1H), 6.76 (s, 2H), 6.99-7.15 (m, 5H). ¹³CNMR (CDCl₃): δ 19.5, 21.1, 23.1, 63.0, 70.4, 127.9, 128.3, 132.0, 134.3,136.7, 139.0, 142.3. Anal: C18H23NO3S. Cal: C, 64.84; H, 6.95; N, 4.20,S, 9.62. Found: C, 65.19; H, 7.04; N, 4.18; S, 9.71.

Preparation of (2S, 4S,5R)-5-methyl-4-phenyl-3-(2,4,6-mesitylsulfonyl)-[1,2,3]oxathiazolidine2-oxide (50): A 50 mL three-necked flask equipped with a mechanicalstirrer, an argon inlet, a thermometer probe and rubber septum, was (1S,2R)-N-(2-hydroxy-1-phenyl-propyl)-2,4,6-mesitylsulfonamide (49) (1.89 g,5.67 mmol), THF (5 mL) and the reaction mixture was cooled to −45° C.Thionyl chloride (1.01 g, 8.50 mmol) was added slowly via syringe in oneportion, followed by slow addition of 2,4,6-collidine (2.10 g, 14.18mmol) in THF (10 mL) for 2-3 hours, and the reaction was monitored byTLC for the disappearance of starting material. The reaction wasquenched with saturated aqueous NaHCO₃ (10 mL), diluted with EtOAc (20mL) and the mixture was warmed to room temperature. The organic layerwas washed with brine (10 mL) and concentrated to dryness. The residuewas added heptane (20 mL), stirred for 2 hours, and filtered to give awhite or off white solid product with 94% de. Crystallization from MTBEfurnished diastereomeric pure product (1.9 g, 88.5%) with >99% de (minordiastereomer not detected by NMR). ¹H NMR (CDCl₃): δ 1.14 (d, J=6.59 Hz,3H), 2.16 (s, 3H), 2.52 (s, 6H). 4.87 (d, J=6.72 Hz, 1H), 5.16 (p,J=6.59, 1H), 6.70 (s, 2H), 7.08-7.13 (m, 5H). ¹³C NMR (CDCl₃): δ 18.07,21.06, 23.00, 65.34, 87.64, 128.20, 128.28, 131.51, 132.11, 132.93.140.59, 144.23. Anal: C18H21NO4S2. Cal: C, 56.97; H, 5.58; N, 3.69; S,16.90. Found: C, 57.16; H, 5.62; N, 3.62; S, 16.94.

(S)-2-Methyl-2-propylsulfinic acid (1S,2R)-1-methyl-2-phenyl-2-(2,4,6-mesitylsulfonylamino)-ethyl ester (51):In a 50 mL two-necked, round-bottomed flask equipped with a magneticstir bar, rubber septum, and argon inlet was placed (2S, 4S,5R)-5-methyl-4-phenyl-3-(2,4,6-mesitylsulfonyl)-[1,2,3]oxathiazolidine2-oxide (50) (0.58 g, 1.53 mmol) dissolved in THF (1.0 mL) and themixture was cooled to −78° C. A solution of t-butyl magnesium chloride(3.1 mL, 1.0 M) in THF was added dropwise via syringe for 30 minuteswith stirring. After 1-2 hours, as monitored by TLC for thedisappearance of the starting material, the reaction was quenched withsaturated aqueous NaHCO₃ (5 mL), and diluted with EtOAc (5 mL). Theaqueous phase was extracted with EtOAc (4 mL) and the combined organicphases were washed with brine (5 mL), dried with (Na₂SO₄) andconcentrated to afford a crystalline product (0.65 g, 97%) with >99% de(minor diasteriomer not detected). ¹H NMR (CDCl₃): δ 1.080 (d, J=6.47Hz, 3H), 1.1749 (s, 9H), 2.163 (s, 3H), 2.485 (s, 6H), 4.394 (dd,J1=8.98 Hz, J2=2.32 Hz, 1H), 4.675 (dq, J1=2.32 Hz, J2=6.53 Hz, 1H),6.61-6.67 (m, 2H), 6.96-7.09 (m, 5H). ¹³C NMR (CDCl₃): δ 19.10, 20.90,21.80, 22.98, 57.85, 61.10, 81.86, 127.58, 128.80, 131.61, 134.98,135.10, 138.50, 141.55.

Preparation of (S)-t-butylsulfinamide ((S)8) from(S)-2-Methyl-2-propylsulfinic acid (1S,2R)-1-methyl-2-phenyl-2-(2,4,6-mesitylsulfonylamino)-ethyl ester (51): A50 mL three-necked round-bottomed flask equipped with a magnetic stirbar and an ammonia condenser was charged with 30 mL of liquid ammoniaunder Ar atmosphere. After the addition of a few crystals of Fe(NO₃)₃,lithium wire (0.05 g, 7.1 mmol) was added in a controlled manner and theinternal temperature was kept around −45° C. When all the lithium wasadded and a gray suspension was formed, the reaction mixture was cooledto −78° C. and a solution of (S)-2-methyl-2-propylsulfinic acid (1S,2R)-1-methyl-2-phenyl-2-(2,4,6-mesitylsulfonylamino)-ethyl ester (51)(0.45 g, 1.03 mmol) in THF (1 mL) was added slowly over a course of 20minutes. Once the addition was complete, the mixture was warmed to −45°C. and stirred for 1 hour, followed by addition of NH₄Cl (0.5 g). Thecold bath was removed, and stirring continued until the mixture reachedambient temperature. The remaining volatile material was removed underreduced pressure. To the remaining residue was added 2 mL water andstirred. EtOAc (5 mL) was added to the mixture and stirred. Afterseparation of the phases, the organic phase was washed with brine (2mL×2). After removal of the organic solvent, the residue was purified bychromatography eluted with EtOAc to afforded (S)-t-butylsulfinamide(0.125 g, 99%) with 99% ee. (HPLC, Chiralpak AS column, 90:10hexane/ethanol; 1.2 mL/min, 222 nm; (R)-TBSA r_(t)=6.6 min; (S)-TBSA,r_(t)=9.4 min.). ¹H NMR (CDCl₃): δ 1.18 (s, 9H), 3.82 (br, s, 2H). ¹³CNMR(CDCl₃): δ 22.1, 55.3.

5.3. Example 3 Sulfinamide Synthesis via (1S,2R)-Norephedrine 4-TolueneSulfonamide

Another method of preparing sulfinamides is represented by Scheme XIV,below:

Preparation of (1S, 2R)-N-(1-hydroxy-2-methyl-1phenyl-ethyl)-4-toluenesulfonamide (53): To a 250 mL threeneck round-bottomed flask equippedwith an overhead stirrer and temperature probe, was charged (1S,2R)-norephedrine (10.0 g, 66.1 mmol), followed by tosyl chloride (12.1g, 63.6 mmol) and the mixture was cooled to 0° C. and stirred for 15minutes. Then Et₃N was added in 2 hours with stirring and the reactionwas monitored by TLC. The reaction was quenched with saturated aqueousNaHCO₃ (50 mL). The organic phase was washed with water (50 mL), 1.0 MHCl (25 mL), water (50 mL) and dried over NaSO₄. Evaporation of theorganic solvent to dryness provided a oily crude product that wascrystallized from MTBE/hexane to give the title product (18.5 g) with90% yield.

(1R, 2S)-Norephedrine 4-toluene sulfonamide was prepared by followingthe same method with 91% yield. ¹H NMR (CDCl₃): δ 0.814 (d, J=6.83 Hz,3H), 2.40 (s, 3H), 3.116 (d, J=4.76 Hz, 1H), 3.42-3.52 (m, 1H),4.786-4.812 (m, 1H), 5.138 (d, J=8.67 Hz, 1H), 7.200-7.316 (m, 7H),7.767 (d, J=8.30 Hz, 2H). ¹³C NMR(CDCl₃): δ 14.49, 55.16, 75.85, 126.19,127.16, 127.69, 128.41, 129.90, 137.84, 140.48, 143.60.

Preparation of (2R, 4R, 5S)-4-methyl-5-phenyl-3-(4-toluenesulfonyl)-[1,2,3]oxathiazolidine2-oxide (54): A 100 mL three-necked flask equipped with a magnetic stirbar, an argon inlet, a thermometer probe and rubber septum, was charged(1S, 2R)-N-(1-hydroxy-2-methyl-phenyl-ethyl)-4-toluenesulfonamide (53)(5.2 g, 17.04 mmol), THF (15 mL) and the reaction mixture was cooled to−45° C. Thionyl chloride (3.04 g, 25.5 mmol) was added slowly viasyringe in one portion, followed by slow addition of 2,4,6-collidine(6.2 g, 51.2 mmol) in THF (30 mL) for 2-3 hours, and the reaction wasmonitored by TLC for the disappearance of starting material. Thereaction was quenched by addition of NaHCO₃ (5.0 g) and saturatedaqueous NaHCO₃ (20 mL), diluted with EtOAc (40 mL) and the mixture waswarmed to room temperature. The organic layer was washed with brine (50mL), dried over Na₂SO₄ and concentrated to dryness. The residue wasadded heptane (50 mL), staged for 1 hour, and filtered to give a whiteor off white solid product (5.6 g, 94%) with 97% de. The product wasused directly in the next step reaction. Diastereomerically purecompound was obtained by crystallization from MTBE.

(2S, 4S, 5R)-3-Tosyl-4-methyl-5-phenyl-2-oxo-1,2,3-oxathiazolidine wasprepared by following the same method with 93% yield and 97% de. ¹H NMR(CDCl₃): δ 0.868 (d, J=6.97 Hz, 3H), 2.545 (s, 3H), 4.210 (p, J=6.48 Hz,1H), 5.572 (d, J=5.98 Hz, 1H), 7.284-7.388 (m, 7H), 7.864-7.892 (m, 2H).¹³C NMR (CDCl₃): δ 16.59, 21.48, 57.12, 92.14, 126.39, 127.68, 128.86,129.16, 130.35, 133.41, 136.62, 145.34.

(R)-2-Methyl-2-propylsulfinic acid (1S,2R)-1-phenyl-2-(4-toluenesulfonylamino)-propyl ester (55): In a 100 mLtwo-necked, round-bottomed flask equipped with a magnetic stir bar,rubber septum, and argon inlet was placed (2R, 4R,5S)-4-methyl-5-phenyl-3-(4-toluenesulfonyl)-[1,2,3]oxathiazolidine2-oxide (54) (4.5 g, 12.8 mmol) dissolved in THF (30.0 mL) and themixture was cooled to −78° C. A solution of t-butyl magnesium chloride(25 mL, 1.0 M) in THF was added dropwise via syringe for 30 minutes withstirring. After 1-2 hours as monitored by TLC for the disappearance ofthe starting material, the reaction was quenched with aqueous NaHCO₃ (30mL), and diluted with EtOAc (40 mL). The aqueous phase was extractedwith EtOAc (20 mL) and the combined organic phases were washed withbrine (40 mL), dried with (Na₂SO₄) and concentrated to afford acrystalline product (5.2 g, 99%) with 97% de.

(S)-2-Methyl-2-propylsulfinic acid (1R,2S)-1-phenyl-2-(4-toluenesulfonylamino-propyl ester was prepared byfollowing the same method with 98% yield and 97% de. ¹H NMR (CDCl₃): δ0.981 (d, J=6.84 Hz, 3H), 1.251 (s, 9H), 2.428 (s, 3H), 3.56-3.675 (m,1H), 4.956 (d, J=2.32 Hz, 1H), 5.841 (d, J=9.77 Hz, 1H), 7.073-7.105 (m,2H), 7.270-7.350 (m, 5H), 7.85-7.879 (m, 2H). ¹³C NMR (CDCl₃): δ 14.88,21.67, 21.90, 54.57, 58.34, 84.82, 125.98, 127.31, 128.36, 128.66,129.86, 137.37, 138.48, 143.46.

Preparation of (R)-t-butylsulfinamide ((R)-TBSA) from(R)-2-Methyl-2-propylsulfinic acid (1S,2R)-1-phenyl-2-(4-toluenesulfonylamino)-propyl ester (55): A 100 mLthree-necked round-bottomed flask equipped with a magnetic stir bar andan ammonia condenser was charged with 50 mL of liquid ammonia under ArAtmosphere. After the addition of a few crystals of Fe(NO₃)₃, lithiumwire (0.3 g, 42.8 mmol) was added in a controlled manner and theinternal temperature was kept around −45° C. when all the lithium wasadded and a gray suspension was formed, the reaction mixture was cooledto −78° C. and a solution of (S)-t-butyl (1S, 2R)-norephedrine sulfinate(2.6 g, 6.3 mmol) in THF (6 mL) was added slowly over a course of 40minutes. Once the addition was complete, as the reaction was monitoredby TLC for the disappearance of the starting material, the mixture wasadded NH₄Cl (4.0 g). The cold bath was removed, and stirring continueduntil the mixture reached ambient temperature. The remaining volatilematerial was removed under reduced pressure. To the remaining residuewas added 5 mL of water and stirred. EtOAc (50 mL) was added to themixture and stirred. After separation of the phases, the organic phasewas washed with brine (6 mL×2). After removal of the organic solvent,the residue was purified with chromatography eluted with EtOAc toafforded (R)-t-butylsulfinamide (0.65 g, 85%) with 96% ee.

Preparation of (S)-t-butyl sulfinamide from(S)-2-Methyl-2-propylsulfinic acid (1R,2S)-1-phenyl-2-(4-toluenesulfonylamino)-propyl ester: The same proceduredescribed above was followed, an furnished the title product in 86%yield and 96% ee. (HPLC, Chiralpak AS column, 90:10 hexane/ethanol; 1.2mL/min, 222 nm; (R)-TBSA r_(t)=6.6 min; (S)-TBSA, r_(t)=9.4 min.). ¹HNMR(CDCl₃): δ 1.18 (s, 9H), 3.82 (br, s, 2H). ¹³C NMR (CDCl₃): δ 22.1,55.3.

5.4. Example 4 Preparation of Enantiomerically Pure Sulfoxides

Stereomerically pure (e.g., enantiomerically pure) sulfoxides can bereadily prepared using methods of the invention. Specific methods areshown below in schemes XV and XVI:

The following can be understood with reference to the schemes shownabove.

Preparation of (S)-t-butyl isobutyl sulfoxide: A THF (40 mL) solution of(S)-tert-butyl (1R, 2S)-aminoindanol mesitylene sulfonamide sulfinate(5.8 g) at −5° C. was slowly added to iBuMgBr (10.5 mL, 2M) in ether.After addition, the reaction mixture was warmed to 10° C., stirred andthe reaction was monitored by TLC. The reaction was quenched by aqueousNH₄Cl, diluted with EtOAc (20 mL) and stirred. The organic phased waswashed with brine (20 mL). Evaporation of the solvent to dryness toafford the crude product that was purified on column eluted with EtOActo give 1.9 g (88%) title product.

Preparation of (R)-t-Butyl isobutyl sulfoxide: The same procedure wasfollowed using (R)-tert-butyl (1S, 2R)-aminoindanol mesitylenesulfonamide sulfinate, and afforded a 90% yield.

¹H NMR (CDCl₃): δ 1.24 (s, 9H), 1.086-1.126 (m, 6H), 2.20-2.30 (m, 2H),2.38-2.45 (m, 1H). ¹³C NMR (CDCl₃): δ 21.78, 23.06, 23.49, 24.12, 52.63,55.00, Anal: Cal: C, 59.20; H, 11.18; S, 19.76. Found: C, 59.39; H,11.36; S, 19.65.

Preparation of (S)-t-butyl methyl sulfoxide from(2S,4S,5R)-3-(2,4,6-mesitylsulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2-oxide (one pot procedure): A solution of(2S,4S,5R)-3-(2,4,6-mesitylsulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene2-oxide (1.44 g, 3.82 mmol) in THF at −15° C. was slowly added tot-BuMgCl (4.0 mL, 1.0M) in THF, and the reaction mixture was stirred(1-2 hours) until the reaction complete as monitored by TLC. Methylmagnesium bromide (4.4 mL, 1.0 M) in THF was then added, the reactionmixture was warmed to room temperature and stirred for 1-2 hours. Thereaction was monitored by TLC. After the reaction mixture was cooled to0° C., the reaction was quenched by addition of saturated aq. NH₄Cl (5mL), stirred and diluted with EtOAc (5 mL). The aqueous phase wasextracted with EtOAc (5 mL×2) and the organic solvent was evaporated.The residue was purified on silica gel eluted with EtOAc/MeOH (8:2) togive the title product (0.38 g, 83%).

Preparation of(S)-t-butyl methyl sulfoxide from (S)-t-Butyl (1S,2R)-norephedrine sulfinate: A THF (2 mL) solution of (S)-t-butyl (1S,2R)-norephedrine sulfinate ester (0.25 g) at −78° C. was added MeMgCl(0.4 mL, 3 M) in THF, and the reaction mixture was warmed slowly to roomtemperature and stirred. The reaction was monitored by TLC. The reactionwas quenched with saturated aqueous NH₄Cl (2 mL), diluted with EtOAc (5mL) and the organic phase was gently evaporated. The residue waspurified on silica gel eluted with EtOAc/MeOH (9:2, v/v) to give 58 mg(79%) title product.

¹H NMR (CDCl₃): δ 1.25 (s, 9H), 2.38 (s, 3). ¹³C NMR (CDCl₃): δ 22.52,31.60, 52.62.

Preparation of (S)-picolinyl t-butylsulfoxide from (S)-tert-Butyl (1R,2S)-aminoindanol 4-toluene sulfonamide sulfinate: To a picolinyl lithiumsolution (2 mL, 0.6 M) in THF at −78° C. was added (S)-t-butyl-(1R,2S)-aminoindanol tosylate sulfinate (130 mg, 0.30 mmol). The mixture waswarmed to room temperature and stirred until the starting material wasconsumed as monitored by TLC. The reaction was quenched by aq. NaHCO₃(20 mL) and diluted with ethyl acetate (20 mL), and the organic phasewas washed with water (20 mL) and brine (20 mL). The organic layer wasconcentrated in vacuo and the residue was purified by chromatographyeluted with ethyl acetate to yield 32 mg of the desired product.

¹H NMR (300 MHz, CDCl₃): δ 1.19 (s, 9H), 3.82 (d, 1H, J=12.3 Hz), 4.07(d, 1H, J=12.3 Hz), 7.26 (m, 1H), 7.45 (d, 1H, J=7.2 Hz), 7.72 (ddd, 1H,J=7.5, 7.5, 1.8 Hz), 8.63 (dd, 1H, J=4.8, 0.9 Hz). ¹³C NMR (75 MHz,CDCl₃): δ 23.29, 54.19, 55.09, 123.19, 132.31, 137.19, 142.77, 150.12.

Preparation of (R)-phenyl t-butylsulfoxide from (S)-tert-Butyl (1R,2S)-aminoindanol mesitylene sulfonamide: A 50 mL flask was charged with(S)-tertbutyl-(1R,2S)-aminoindanol mesitylene sulfonamide (1.12 g, 3.0mmol) and THF (3 mL) and the mixture was cooled to −20° C. To themixture was added phenyl magnesium bromide (9 mL, 1.0 M in THF), thereaction mixture was stirred at 0° C. and the reaction was monitored byTHC. The reaction was quenched by aqueous NaHCO₃ (20 mL) and dilutedwith ethyl acetate (70 mL), and the organic phase was washed with water(50 mL) and brine (50 mL). The organic layer was concentrated in vacuoand the residue was purified by chromatography eluted by 2:1hexane:ethyl acetate to give 390 mg of (R)-phenyl t-butylsulfoxide.

¹H NMR (300 MHz, CDCl₃): δ 1.20 (s, 9H), 7.53 (m, 3H), 7.63 (m, 3H). ¹³CNMR (75 MHz, CDCl₃): δ 23.04, 56.02, 126.57, 128.63, 131.40, 140.23.Anal. Calcd for C₁₀H₁₄OS: C, 65.89; H, 7.74; S, 17.59. Found: C, 65.91;H, 7.78; S, 17.65. Optical rotation: C=1.0, CHCl₃ [α]²² _(D)=+174.6(lit.=+175).

While the invention has been described with respect to particularembodiments, it will be apparent to those skilled in the art thatvarious changes and modifications may be made without departing from thespirit and scope of the invention as defined in the claims. Suchmodifications are also intended to fall within the scope of the appendedclaims.

1. A compound of Formula 3:

wherein n is 0 to 3; L is SO_(m)R₃, wherein m is 0 to 3; R₁ and R₂together form a cyclic structure or each of R₁ and R₂ is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle; R_(1′) andR_(2′) together form a cyclic structure or each of R_(1′) and R_(2′) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted aralkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheterocycle; R_(a) and R_(b) together form a cyclic structure or each ofR_(a) and R_(b) is independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; and R₃ is a polymer boundalkyl, aryl or heteroalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted ether, substituted or unsubstituted ester, substituted orunsubstituted ketone, substituted or unsubstituted phosphonate,substituted or unsubstituted phosphonic acid ester, substituted orunsubstituted phosphinoyl, substituted or unsubstituted sulfide,substituted or unsubstituted sulfone, substituted or unsubstitutedsulfinyl imine, substituted or unsubstituted heterocycle, or —NR₄R₅,wherein R₄ and R₅ together with the nitrogen atom to which they areattached form a heterocycle or each of R₄ and R₅ is independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aralkyl,substituted or unsubstituted aryl, substituted or unsubstituted ether,substituted or unsubstituted sulfide, or substituted or unsubstitutedheterocycle.
 2. The compound of claim 1, which has the followingstructure:


3. The compound of claim 1, which has the structure:


4. The compound of claim 3, which has one of the followingstereochemistries:


5. The compound claim 1 wherein R₁ is aryl or alkyl.
 6. The compound ofclaim 1 wherein R₂ is aryl or alkyl.
 7. The compound of claim 1 whereinR₃ is substituted or unsubstituted lower alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroalkyl, oraryl.
 8. The compound of claim 6, wherein R₃ is halogenated phenyl,3-methylphenyl, 4-methylphenyl, 1,3,5-trimethylphenyl,4-(tert-butyl)phenyl, 2-mesityl, tolyl, 2,4,6-triisopropylphenyl, phenylor biphenyl.
 9. The compound of claim 7 wherein R₃ is 2-mesityl, tolylor triisopropylphenyl.
 10. The compound of claim 1, which is of theFormula 9:

or a salt, solvate, clathrate, or stereomerically pure form thereof. 11.The compound of claim 10, wherein R₃ is halogenated phenyl,3-methylphenyl, 2-methylphenyl, 2-mesityl, tolyl, 4-(tert-butyl)phenyl,2,4,6-triisopropylphenyl, phenyl or biphenyl.
 12. The compound of claim1, which is of the Formula 10:

or a salt, solvate, clathrate, or stereomerically pure form thereof,wherein each R₁₀ is independently substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,a primary, secondary, or tertiary amine, or a halogen atom; n is aninteger of 1 to 4; and m is an integer of 0 to
 4. 13. The compound ofclaim 12, wherein n is 1 and m is 0, 1 or
 2. 14. The compound of claim13, wherein R₃ is halogenated phenyl, 3-methylphenyl, 2-methylphenyl,2-mesityl, tolyl, 4-(tert-butyl)phenyl, 2,4,6-triisopropylphenyl, phenylor biphenyl.
 15. The compound of claim 10 or claim 12, wherein saidcompound is stereomerically pure.